Diazepine derivatives

ABSTRACT

Compounds of the class of 2-(aminomethyl)-6-phenyl-4H-striazolo(1,5-a)(1,4)benzodiazepines, their 5-oxides and the pharmaceutically acceptable acid addition salts of said compounds and their 5-oxides have valuable pharmacological properties, in particular anticonvulsant effectiveness, and are active ingredients for therapeutic preparations. Specific embodiments are 2-((dimethylamino)-methyl)-6-phenyl-8-chloro-4H-striazolo(1,5 -a)(1,4)benzodiazepine, 2-((methylamino)-methyl)-6phenyl-8-chloro-4H-s-triazolo(1,5 -a)(1,4)benzodiazepine, 2((dimethylamino)-methyl)-6-(o-fluorophenyl)-8-chloro-4H-striazolo(1,5 -a)(1,4)benzodiazepine, 2-((methylamino)-methyl)-6(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5 -a)(1,4)benzodiazepine and 2-((methylamino)-methyl)-6-(o-chlorophenyl)-8-chloro-4H-striazolo(1,5 -a)(1,4)benzodiazepine.

United States Patent Gagneux et al.

[ Apr. 15, 1975 DIAZEPINE DERIVATIVES Inventors: Andre Gagneux, Basel;Roland Heckendorn, Arlesheim; Rene Meier, Buus, all of SwitzerlandAssignee: Ciba-Geigy Corporation, Ardsley,

Filed: July 14, 1972 Appl. No.: 272,088

Foreign Application Priority Data July 23, l97l Switzerland 10885/71 US.Cl 260/247.5 EP; 260/141; 260/193; 260/247.1; 260/247.2 R; 260/268 TR;260/293.59; 260/308 R; 424/248; 424/250; 424/267; 424/269 Int. Cl. C07d57/02; CO7d 99/02 Field of Search..... 260/308 R, 293.59, 268 TR,260/247.5 R

References Cited UNITED STATES PATENTS ll/l972 Tawada et al 260/308 RPrimary Examiner-Alton D. Rollins Attorney, Agent, or Firm.loseph G.Kolodny; John J. Maitner; Theodore O. Groeger [57] ABSTRACT4H-s-triazolo[ l ,5-a][ 1,4]benzodiazepine, 2-[(methylamino)-methyl]-6-phenyl-8-chloro-4H-striazolo[1,5-a][1,4]benzodiazepine,2-

[(dimethylamino)-methyl]-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo[l,5-a][1,4]benzodiazepine, 2- [(methylamino)-methyl ]-6-(o-fluorophenyl )-8-chloro- 4H-s-triazolo[ l,5-a][1,4]benzodiazepine and 2- [(methylamino)-methyl]-6-(o-chlor0phenyl)-8-chloro-4H-striazolo[l,5-a][1,4]benzodiazepine.

20 Claims, No Drawings DIAZEPINE DERIVATIVES DETAILED DESCRIPTION Thepresent invention relates to new diazepine derivatives. to processes fortheir production. to therapeutic preparations containing the newcompounds. and to the use thereof.

The compounds according to the invention correspond to the generalformula l wherein R, represents hydrogen. or an alkyl group having from1 to 3 carbon atoms.

R- and R;,. independently of each other. represent a hydrogen atom. analkyl or hydroxyalkyl group having from l to 6 carbon atoms. or anaralkyl group having from 7 to 9 carbon atoms. whereby. when R;- and Rsimultaneously represent alkyl groups as aforesaid. these alkyl groupsmay optionally be bound together in the B- or y-position either directlyor via an oxygen atom or imino group. or alkylimino or hydroxyalkyliminogroup having at most 4 carbon atoms. and wherein each of the rings A andB. independently of the other. is unsubstituted or substituted by one ormore chlorine atoms. fluorine atoms. bromine atoms. trifluoromethylgroups. nitro groups and/or alkyl and/or alkoxy groups having from I to6 carbon atoms.

The invention also relates to the S-osides of the compounds of thegeneral formula I. and to the addition salts of the compounds of thegeneral formula I and of their S-oxides with inorganic and organicacids.

In the compounds of the general formula I. R, is. as alkyl group. e.g.the methyl. ethyl or propyl group. Suitable alkyl groups as substituentsof the rings A and B each having I to 6 carbon atoms are. e.g. themethyl. ethyl. propyl. isopropyl. butyl. isobutyl. tert.butyl. pentyl.isopentyl. neopentyl. tert.pentyl or hexyl group: and suitable alkosygroups having 1 to 6 carbon atoms are. e.g. the methoxy. ethoxy.propoxy. isopropoxy. butoxy. isobutoxy. pcntyloxy. isopentyloxy orhexyloxy group. Preferably. however. substituents of the rings A and Bare fluorine. chlorine or bromine atoms. trifluoromethyl groups and/ornitro groups. As alkyl groups having I to 6 carbon atoms. R, and R are.e.g. ethyl. propyl. isopropyl. butyl. isobutyl. pentyl. isopentyl orhexyl groups. and preferably methyl groups: as hydroxyalkyl groupshaving at most 6 carbon atoms. R: and R;, are. e.g. Z-hydroxypropy'l.3-hydroxypropyl. 2- hydroxybutyl. B-hydroxybutyl.Z-hydroxy-l-methylpropyl. Z-hydroxypentyl. Z-hydroxyhexyl and. inparticular. Z-hydroxyethyl groups; and as phenylalkyl groups having atmost 9 carbon atoms. R- and R are. e.g.. benzyl. phenethyl. a. o-. morp-methylbenzyl. 3- phenylpropyl or a-methylphenethyl groups.

Alkyl groups R: and R bound together in the B- or 'y-position in theabove defined manner form. together with the adjacent nitrogen atom.e.g. the l-pyrrolidinyl. piperidino. hexahydro-lH-azepin-l-yl.morpholino. lpiperazinyl or hexahydro-lH-l.4-diazepin-l-yl group. Thetwo last-mentioned groups can be substituted in the -l-position. i.e. inthe imino group. e.g. by a methyl. ethyl. propyl. isopropyl. butyl.isobutyl. 2- hydrosyethyl. Z-hydroxypropyl. 3-hydroxypropyl or 3-hydrosybutyl group. whilst all aforementioned rings on carbon atoms can.moreover. be substituted by ethyl. propyl or. in particular. methylgroups.

A preferred class of diazepine derivatives are those. wherein R, ishydrogen and wherein the rings A and B are unsubstituted or substitutedby a single substituent defined under formula l. These diazepinederivatives correspond to the general formula la and R, and Rindependently of each other. represent a hydrogen. fluorine. chlorine orbromine atom. a trifluoromethyl or nitro group or an alkyl or alkoxygroup having from 1 to 6 carbon atoms.

The radical R, is preferably in the 8-position and is. in particular.one of the mentioned halogen atoms. especially chlorine. also the nitrogroup or the trifluoromethyl group. The radical R is preferably hydrogenor a fluorine. chlorine or bromine atom or the trifluoromethyl group inany desired position. particularly. however. it is hydrogen or is afluorine or chlorine atom in the o-position.

The compounds of the general formula I. their 5- oxides and the additionsalts of the compounds of the general formula l and of their 5-oxideswith inorganic and organic acids possess valuable pharmacologicalproperties. They have. in particular. an anticonvulsive action. such ascan be shown. for example. on the mouse in the pentetrazoleconvulsiontest after administration of oral doses of from ca. 0.4 mg/kg. as wellas in the strychnine convulsion test and in the electroshock test. Thefollowing are of special importance: 2- [(dimethylamino )-methyll-6-phenyl-8-chloro-4H-striazolo[ l.5-a][ 1.4]benzodiazepine. 2-

and [(methylamino )-methyl ]-6-( o-chlorophenyl )-8-chloro-4H-s-triazolol l.5-al[ l.-l]benzodiazepine. and their pharmaceuticallyacceptable acid addition salts. Compared with their anticonvulsiveaction. the sedative action of the new compounds is less pronounced. Byvirtue of the mentioned properties and others. which can be determinedby selected standard tests [cp. W. Theobald and H. A. Kunz.Arzneimittelforsch. 13. I22 (1963 and also W. Theobald et al..Arzneimittelforsch. l7. Sol 1967)]. the compounds of the general formulal. their S-oxides. and the corresponding pharmaceutically acceptableaddition salts with inorganic and organic acids constitute activesubstances for tranquilisers and anticonvulsants which can beadministered. for example. for the treatment of conditions of stress andagitation with no. or with only negligible. effect on vigility; as wellas for the treatment of epilepsy.

The compounds of the general formula I. their oxides and thecorresponding acid addition salts are produced according to theinvention by the reaction of a reactive ester of a compound of thegeneral formula ll (1H CH C wherein R. has the meaning given underformula I. and the rings A and B can be substituted as defined there. orof the S-oxide of such a compound. with a compound of the generalformula III (IIT) wherein R and R have the meaning given under formulal. or with an alkali metal derivative of such a compound: and.optionally. the conversion of the obtained reaction product into anaddition salt with an inorganic or organic acid.

Suitable reactive esters of hydroxy compounds of the general formula llare. e.g. sulphonic acid esters such as the methanesulphonic acidesters. the oand ptoluenesulphonic acid esters. the 0- orp-nitrobenzenesulphonic acid esters. or the 0- orp-chlorobenzenesulphonic acid esters. Further suitable reactive estersof compounds of the general formula ll are their hydrohalic acid esters.especially chlorides or bromides. as well as the iodides produced insitu from them. An excess of the basic compound to be reacted of thegeneral formula II] can serve as reaction medium. and simultaneously asacid-binding agent. It is also possible to use as the reaction medium.in addition to. or in place of. the excess compound. an inert organicsolvent. e.g. a lower alkanol such as methanol. ethanol. propanol.isopropanol or butanol. a ketone such as acetone or methyl ethyl ketone.also. e.g. dioxane. tetrahydrofuran. dimethylformamide ordimethylsulphoxide. whereby. optionally. the compound of the generalformula lll may be also used in excess as an aqueous solution: or.alternatively. it is'possible to use. instead of this excess. or inaddition to it. another acid-binding agent. e.g. a tertiary organic basesuch as ethyldiisopropylamine or collidine. or an inorganic basicsubstance such as. e.g. potassium carbonate.

lf. instead of the compound of the general formula III. an alkali metalderivative of such a compound is used as reaction component. e.g. asodium. lithium or potassium derivative. then it is preferable to usehydrocarbons such as benzene. toluene or xylene. ethereal liquids suchas 1.2-dimethoxyethane. tetrahydrofuran or dioxane. or acid amides suchas dimethylformamide or hexamethylphosphoric acid triamide. orsulphoxides such as dimethylsulphoxide. as solvents. The formation ofthe alkali metal derivatives of the compounds of formula III. with theexception of ammonia. is preferably effected in situ. e.g. by additionof at least the equimolar amount of alkali metal hydride such as sodiumhydride. alkali metal amide such as sodium or lithium amide. or of analkali-metaI-organic compound such as phenylor butyllithium. Thereaction temperatures are preferably between 0 and C. or the boilingtemperature of the employed reaction medium. The preparation of thecompounds of the general formula II and their reactive esters isdescribed below.

A second process for the production of compounds of the general formulaI wherein R and R are hydrogen atoms. whilst R has the meaning givenunder formula I. and the rings A and B can be substituted as definedthere. and of their S-oxides and the corresponding acid addition salts.comprises the reduction of a compound of the general formula IV CH N M.It

wherein R has the meaning given under formula I. and the rings A and Bcan be substituted as defined there. or of the 5-oxide of such acompound; and. optionally. the conversion of the obtained reactionproduct into an addition salt with an inorganic or organic acid.

The reduction of the azides of the general formula IV. the preparationof which is described below. can be carried out both by chemical methodsand by catalytic hydrogenation. e.g. in the presence of palladiumcharcoal catalysts. platinum oxide or Raney nickel. in an organicsolvent such as dioxane. ethanol. methanol or tetrahydrofurat'i. at roomtemperature and under normal pressure. A suitable chemical method is. inparticular. the reduction with tin(ll)-chloride in loweralkanolicaqueous. especially ethanolic-aqueous. alkali solution.particularly sodium hydroxide solution. at temperatures of between ca.and the boiling temperature of the reaction mixture. preferably betweenca. 0 and room temperature.

A third process for the production of compounds of the general formula Iof which the radical R is hydrogen. or in which the lower alkyl groupsR; and R are bound in the B- or y-position by an imino group. whilst R,has the meaning given under formula I. and the rings A and B can besubstituted as defined there. as well as of oxides of such compounds andthe corresponding acid addition salts. comprises the hydrolysis of acompound of the general formula V CH N A l \N N l (v) CH R wherein Rrepresents an acyl radical. or a lower alkyl group bound to a loweralkyl group R in the B- or 'y-position by an acylimino group.

R and R- have the meanings given under formula I. and the rings A and Bcan be substituted as defined there. or of the S-oxide of such acompound: and. optionally. the conversion of the obtained reactionproduct into an addition salt with an inorganic or organic acid.

In the starting materials of the general formula V. the preparation ofwhich is subsequently described. R or the acyl radical of the iminogroup is. in particular. a lower alkanoyl group such as the acetyl orformyl group. the cyano group. a lower alkoxycarbonyl group such as themethoxycarbonyl. ethoxycarbonyl or tert- .butoxycarbonyl group. aphenoxycarbonyl or benzyloxycarbonyl group. also a correspondingthiocarbonyl group. or the acyl radical of another monofunctionalderivative ofcarbonic acid such as. e.g. the chlorocarbonyl group. or anarenecarbonyl group such as the benzoyl group.

Hydrolysis can be performed with the aid of an alkali metal hydroxide.e.g. potassium or sodium hydroxide. at a temperature of ca. 50 to'l2()C.e.g. in a higher boiling organic solvent containing hydroxyl groups.

such as. e.g. ethylene glycol or diethylene glycol. or in a lowermonoalkyl ether of such a glycol. or in a lower alkanol such as methanolor ethanol. Furthermore. hydrolysis can also be carried out in an acidmedium. e.g. with hydrogen bromide or hydrogen chloride in acetic acid.or with alkanolic hydrochloric acid. at a temperature of ca. 50 to lC orat the boiling temperature of the reaction mixture.

The compounds of the general formula ll. on which the reactive estersrequired as starting materials for the first process are based. areobtained. for example. starting with compounds of the general formula VICO (VI) wherein the rings A and B can be substituted as defined underformula I. Such compounds are described in the literature. e.g.Z-amino-S-chlorobenzophenone lcp. F. D. Chattaway. .l.Chem.Soc. 85. 344(1904)]. or 2- amino-Z'.5-dichlorobenzophenone ]cp. L. H. Sternbach etal.. J. Org. Chem. 26. 4488 (196] )1. The cornpounds of the generalformula Vl are diazotised. and the obtained diazonium salts subsequentlycoupled with (Z-chloroalkaneamido)-malonic acid diethyl esters of whichthe alkaneamido group contains 2 to 5 carbon atoms. especially with(Z-chlormtcetamido)- malonic acid diethyl ester ]cp. Ajay Kumar Bose. J.Indian Chem; Soc. 31. l()8l 10 (1954)]. to give the corresponding(Z-chloroalkaneamido Z-benzoylphenylazo )-malonic acid diethyl esters.particularly (2- ChlOI'02lCt3I21l'llldO)-( Z-benzoyl-phenylazo )malonicacid diethyl esters. The coupling products are then converted. bytreatment with at least the double-molar amount. preferably the threetofourfold amount. of sodium hydroxide and subsequent neutralisation. intothe compounds of the general formula VII COOH l N N I ll (VII) nia orwith hexamethylenetetramine. with the chlorine atom being thus replacedby the amino group. and simultaneously. with elimination of water. ringclosure occurring to give carboxylic acids of the general formula lXwherein R, has the meaning given under formula I. and the rings A and Bcan be substituted as defined there. It is also possible. however. tofirstly react the compounds of the general formula Vll with sodiumazide. in the presence of potassium iodide. to compounds of the generalformula Vlll ioou i l1 CH R (VIII) 0 0 wherein R has the meaning givenunder formula I. and the rings A and B can be substituted as definedthere: and to then cyclise these compounds with triphenylphosphine. withevolution of nitrogen. to compounds of the general formula lX.

The carboxylic acids of the general formula [X are converted in a mannerknown per se. e.g. with ethanol or methanol containing hydrogenchloride. into their ethyl or methyl esters; and these reduced withlithium aluminium hydride. in an ethereal solvent such astetrahydrofuran and at temperatures of around 0C. to compounds of thegeneral formula ll. The ethyl esters of the carboxylic acids of thegeneral formula IX required for the reducation can also be obtained bythe treatment of the aforementioned coupling products with at most thedouble-molar amount of sodium hydroxide under mild reaction conditions.i.e. at room temperature and with neutralisation before processing: andthe subsequent reaction of the ethyl esters of carboxylic acids of thegeneral formula VI! obtained as the main product.

LII

in a manner analogous to that for the free acids. withhexamethylenetetramine in absolute ethanol.

The compounds of the general formula ll obtained by reduction areconverted in a manner known per se. e.g. by reaction with a sulphonicacid chloride such as methanesulphonic acid chloride orp-toluenesulphonic acid chloride. in an inert organic solvent such asmethylene chloride. in the presence of an organic base such astriethylamine or ethyl-diisopropylamine. or by reaction with thionylchloride or phosphorus tribromide and. optionally. subsequently withpotassium iodide. into suitable reactive esters.

The compounds of the general formula IV serving as starting materialsfor the second process are produced by the reaction of reactive estersof compounds of the general formula ll. e.g. methanesulphonic acidesters. with alkali metal azides such as sodium azide. in inert organicor organic-aqueous solvents. such as. e.g. aqueous acetone.

The starting materials of the general formula V used in the thirdprocess. in which R is an acyl group. are obtained. for example.analogously to the firstmentioned process by employing. instead of analkali metal compound of a starting material of the general formula 11].e.g. an alkali metal compound of a formamide. acetamide or cyanamidesubstituted in the amide group by R. or of a carbamic acid-lower alkylester. -phenyl ester or -benzyl ester substituted on the nitrogen atomby R.

The compounds of the general formula I obtained by the processesaccording to the invention. and also the S-oxides of these compounds.are optionally converted. in the usual manner. into their addition saltswith inorganic and organic acids. For example. the acid desired as saltcomponent is added to a solution of a compound of the general formula Iin an organic solvent. Organic solvents in which the formed salt isdifficultly soluble are preferably chosen for the reaction. so that thesalt can be separated by filtration. Such solvents are. e.g. methanol.ether. acetone. methyl ethyl ketone. acetone/ether. acetone/ethanol.methanol/ether or ethanol/ether.

It is possible to use as pharmaceutical active substances. instead offree bases. pharmaceutically acceptable acid addition salts. i.e. saltswith such acids of which the anions are not toxic in the case of thedosage amounts in question. Moreover. it is of advantage if the salts tobe used as pharmaceutical active substances crystallise well and arenot. or only slightly. hygroscopic. The following may be used. forexample. for salt formation with compounds of the general formula 1:hydrochloric acid. hydrobromic acid. sulphuric acid. phosphoric acid.methanesulphonic acid. ethanesulphonic acid. Z-hydroxyethanesulphonicacid. acetic acid. lactic acid. succinic acid. fumaric acid. maleicacid. malic acid. tartaric acid. citric acid. benzoic acid. salicylicacid. phenylacetic acid. mandelic acid and embonic acid.

The new active substances are administered orally. rectally orparenterally. The dosage amount depends on the mode of administration.on the species. on the age and on the individual condition. The dailydoses of the free bases. of their 5-oxides. or of pharmaceuticallyacceptable salts of the free bases vary between 0.02 mg/kg and 2 mg/kgfor warm-blooded animal's. Suitable dosage units. such as dragees.tablets. suppositories or ampoules. preferably contain 0.5-25 mg of anactive substance according to the invention.

Dosage units for oral administration contain as active substancepreferably between 1-50 percent of a compound of the general formula 1.or of a pharmaceutically acceptable salt thereof. The dosage units areprepared by the combination of the active substance with. e.g. solidpulverulent carriers such as lactose. saccharose. sorbitol. mannitol:starches such as potato starch. maize starch or atnylopectin. alsolaminaria powder or citrus pulp powder; cellulose derivatives orgelatine. optionally with the addition of lubricants such as magnesiumor calcium stearate or polyethylene glycols. to form tablets or drageecores. The dragee cores are coated. for example. with concentrated sugarsolutions which may also contain. e.g. gum arabic. talcum and/ortitanium dioxide; or with a lacquer dissolved in readily volatileorganic solvents or solvent mixtures. Dyestuffs can be added to thesecoatings in order to facilitate. for example. identification of thevarious doses of active substance.

Other suitable oral dosage units are hard gelatine capsules. as well assoft closed capsules made from gelatine and a softener. such asglycerin. The hard capsules contain the active substance preferably as agranulate. in admixture. for example. with fillers such as maize starch.and/or lubricants such as talcum or magnesium stearate. and optionallystabilisers such as so-- dium metabisulphite (Na- 5 or ascorbic acid. Insoft capsules. the active substance is preferably dissolved or suspendedin suitable liquids such as polyethylene glycols. to which likewisestabilisers may be added.

Suitable dosage units for rectal administration are. e.g. suppositoriesconsisting of a combination of an active substance and a suppositoryfoundation substance.

The following. for example. aresuitable as base substances: natural orsynthetic triglycerides. paraffin hydrocarbons. polyethylene glycols orhigher alkanols. Hard gelatine capsules consisting of a combination ofthe active substance and a foundation substance are likewise suitable.Suitable foundation substances are. e.g. liquid triglycerides.polyethylene glycols or paraffin hydrocarbons.

Ampoules for parenteral administration. particularly for intramuscularadministration. preferably contain a water-soluble salt of an activesubstance in a concentration of preferably 0.1 2 percent. optionallytogether with suitable stabilisers and buffer substances. in aqueoussolution.

The following specifications further illustrate the production oftablets. dragees. capsules. suppositories and ampoules:

a. An amount of 50 g of 2-[(dimethylamino)- methyl]-6-phenyl-8-chloro-4H-s-triazolo[ 1.5- all 1.4]benzodiazepine is mixedwith 175.80 g of lactose and 169.70 g of potato starch; the mixture ismoistened with an alcoholic solution of 10 g of stearic acid. and thengranulated through a sieve. After the granulate has dried. the followingingredients are mixed in: 160 g of potato starch. 200 g of talcum. 2.50g of magnesium stearate and 32 g of colloidal silicon dioxide: themixture is subsequently pressed to obtain 10.000 tablets each weighing80 mg and each containing 5 mg of active substance; the tablets mayoptionally be provided with grooves to render possible a more preciseadjustment of the dosage amount. It is also possible to use. as activesubstance. the same amount of 2- 10 (piperidinomethyl)-6-phenyl-8-ch1oro-4H-striazolol 1.5-all 1.4]benzodiazepine.

b. A granulate is produced from 50 g of 2- I (dimethylamino )-methyl]-6-(o-fluorophenyl )-8- chloro-4H-s-triazolo 1.5-a][1.4]benzodiazepine. 175.90 g of lactose and the alcoholic solution of 10g of stearic acid: after drying. the granulate is mixed with 56.60 g ofcolloidal silicon dioxide. 165 g oftalcum. 20 g of potato starch and2.50 g of magnesium stearate: and the mixture finally pressed to obtain10.000 dragee cores. These are then coated with a concentrated syrupmade from 502.28 g of crystallised saccharose. 6 g of shellac. 10 g ofgum arabic. 0.22 g of dyestuff and 1.5 g of titanium dioxide; the coateddragees are finally dried. The obtained dragees each weigh 100 mg andeach contain 5 mg of active substance.

c. To produce 1000 capsules each containing 2 mg of active substance. anamount of 2 g of 2- l(methylamino)-methyl]-6-(o-fluorophenyl-8-chloro-4H-s-triazolol 1.5-a][ 1.4]benzodiazepine hydrochloride is mixed with256 g of lactose; the mixture is uniformly moistened with an aqueoussolution of 2 g of gelatine. and then granulated through a suitablesieve (e.g. sieve 111 according to Ph.Helv. V). The granulate is mixedwith 10.0 g of dried maize starch and 15.0 g of talcum. and the mixtureevenly filled into 1000 hard gelatine capsules. size I. It is alsopossible to use. as active substance. the same amount of 2-[(methylaminomethyl ]-6-( o-fluorophenyl l-8-chloro-4H-striazolol 1.5-a][1.4lbenzodiazepine-fumarate-( 1:2).

d. A suppository mixture is prepared from 1.0 g of 2-[(dimethylamino)-methyl]-6-pheny1-8-chloro-4H-striazolol 1.5-a1l1.4]benzodiazepine and 169.0 g of adeps-solidus; from the preparedmixture are then poured 100 suppositories each containing 10 mg ofactive substance.

e. A solution of 2.0 g of 2-l(methylamino)-methyl]-b-phenyl-8-chloro-4H-s-triazolol 1.5-a H 1.4 ]benzodiazepinehydrochloride in one litre of water is filled into 1000ampoules. and these then sterilised. An ampoule contains a 0.2 percentsolution of 2 mg of active substance.

The following examples further illustrate the production of the newcompounds of the general formula I and of intermediates not hithertodescribed: these examples. however. do not in any way limit the scope ofthe invention. Temperatures are expressed in degrees Centigrade.

EXAMPLE 1 a. An amount of 8.05 (0.02 mole) of methanesulphonic acidester of 6-phenyl-8-chloro-4H striazolol1.5-all1.4]benzodiazepine-Z-methanol is dissolved in ml ofdimethylsulphoxide; the solution is then added dropwise at 510. withstirring. to a mixture of 10 g (0.09 mole) of 40.5 percent aqueousdimethylamine solution and 20 ml of dimethylsulphoxide. The reactionmixture is then allowed to warm up to room temperature. and is stirredfor a further hour at 2025. It is thereupon poured on 0.5 litre oficecold water. and extraction carried out twice with 250 ml of benzeneeach time. The combined benzene extracts are washed five times with mlof water each time; they are dried over sodium sulphate and concentratedin vacuo. The residue is dissolved in chloroform. and the solutionchromatographed through a column containing g of basic aluminium oxide.After elution with chloroform. concentration of the eluate byevaporation. and recrystallisation of the residue from cyclohexane.2-[(dimethylamino)-methyl]-6-phenyl-8- chloro-4H-s-triazolo[ 1 .5-a 1.-1]benzodiazepine. M.P. 133135. is obtained.

The methanesulphonic acid ester required as starting material isproducedas follows:

b. A solution of 58.0 g (0.25 mole) of 2-amino-5- chlorobenzophenonelcp. F. D. Chattaway. J.Chem.-

Soc. 85. 344 (1904)] in 310 ml of glacial acetic acid/- cone.hydrochloric acid (4:1) is diazotised at room temperature. whilststirring is maintained. with 50 ml (0.25 mole) of aqueous sodium nitritesolution. An amount of 150 g of ice is added to the obtained diazoniumsalt solution. followed by the rapid addition dropwise of a solution of52.4 g (0.208 mole) of (2- chloroacetamido)-malonic acid diethyl esterlcp. Ajay Kumar Bose. .l.lndian ChenrSoc. 31. 108-1 1954)] in 600 ml ofacetone. An addition is subsequently made dropwise at 5-10. in thecourse of minutes. of a solution of 276.0 g (2 moles) of potassiumcarbonate in 500 ml of water; stirring is continued for one hour. andbenzene and saturated sodium chloride solution are then added. Thebenzene solution is separated. washed with saturated sodium chloridesolution. dried over sodium sulphate. and concentrated by evaporation toobtain 121 g of crude (2-benzoyl-4-chlorophenylazo)-(2-chloroacetamido)-malonic acid diethyl ester. This crude product isdissolved in 1.5 litres of dioxane; an amount of 36 g (0.9 mole) ofsodium hydroxide dissolved in 2 litres of water is then added. themixture stirred for 30 minutes. and the dioxane evaporated off in vacuo.The residue is diluted with 500 ml of water. and 20 g of active charcoaladded; the mixture is well stirred and then filtered through purifieddiatomaceous earth. An addition is made to the filtrate. with thoroughstirring. of 2N hydrochloric acid until an acid reaction to a congo-rcdindicator is obtained: the precipitated carboxylic acid is filtered offunder suction. washed with water and then recrystallised from hotmethanol. The obtained crystals. containing an equimolar amount ofmethanol. of 1-(2-benzoyl-4-chlorophenyl )-5- (chloromethyl)-1Hl.2.4-triazole-3-carboxylic acid sinter at 137l38 and melt. withdecomposition. at l69l 7 1.

c. An amount of 33.2 g (0.200 mole) of potassium iodide is dissolved in85 ml of water. and the obtained solution diluted with 850 ml ofdioxane; an addition is made at with stirring. of 71.5 g (0. l 75 mole)of the compound produced according to b). and the solution heated for 1hour at 45-50. An amount of 0.5 litre of concentrated aqueous ammoniasolution is thereupon added: the mixture is heated for 2 hours at 4550.and concentrated in vacuo. The residue is dissolved in 2 litres ofwater. and an addition then made of 2N hydrochloric acid until thesolution shows an acid reaction to a congored indicator. The freecarboxylic acid precipitates; it is filtered off under suction. washedwith water until neutral. subsequently washed with methanol. and driedin vacuo at l20-130. The obtained 6-phenyl-8- chloro-4-H-s-triazolo[1,5-a][l ,4]benzodiazepine -2 carboxylic acid decomposes at 170.

This carboxylic acid can also be produced according to d) from thechloromethyl compound obtained by procedure b):

d. An amount of 0.408 g (0.001 mole of the chloromethyl compoundobtained according to b). containing an equimolar amount of methanol.and 0.320 g (0.003 mole) of hesamethylenetetramine is dissolved in 20 mlof ethanol. and the solution refluxed for 12 hours. The solution is thenconcentrated at 40 in vacuo. and the residue dissolved in 20 ml of 0.05Nsodium hydroxide solution: 2N hydrochloric acid is then added until thesolution shows an acid reaction to a congo-red indicator. and theprecipitated crude product processed as under c). The obtained6-phenyl-8-chloro-4H-striazolo[ l.5a][ l.4]benzodiazepine-2-carboxylicacid melts at 170.

e. An amount of 6.77 g (0.020 mole) of 6-phenyl-8- ch1oro-4H-s-triazolo[1.5-a][ 1 .4lbenzodiazepine-2- carboxylic acid [produced according to c)or d)] is suspended in 250 ml of abs. ethanol. Whilst stirring andrefluxing are maintained. the solution is saturated with hydrogenchloride gas. The obtained clear solution is refluxed for a further 10hours. and afterwards concentrated at 40 in vacuo. The residue isdissolved in ml of ice-cold 5% sodium bicarbonate solution and 100 ml ofmethylene chloride; the organic phase is separataed. washed with water.dried over sodium sulphate. and concentrated at 40 in vacuo. The crudeviscous residue is refluxed with 100 ml of ether for one hour. duringwhich process crystallisation occurs. After cooling to 0, the crystalsare filtered off under suction and washed with ether to obtain6-phenyl-8-chloro-4- H-s-triazolo[ 1.5-a][l.4]benzodiazepine-2-carboxylic acid ethyl ester. M.P. l37138.

f. An amount of l 1.0 g (0.030 mole) of 6-phenyl-8-ch1oro-4H-s-triazolo-[ l .5-a][ 1.4]benzodiazepine-2- carboxylic acidethyl ester dissolved in 1 10 ml of abs. tetrachlorofuran is addeddropwise in the course of 1 hour. with ice cooling. to a suspension of2.3 g (0.06 mole) of lithium aluminium hydride in ml of abs.tetrahydrofuran. The mixture is stirred for a further 30 minutes at 0-5.and l 1.5 ml of 1N sodium hydroxide solution then added dropwise. Theinorganic salts are filtered off; the filtrate is then concentrated invacuo. the residue dissolved in 200 ml of chloroform. the solutionwashed with 1N sodium hydroxide solution and then with water. Afterdrying over sodium sulphate. the chloroform solution is concentrated invacuo. and the residue crystallised from isopropanol. After drying. theobtained 6-phenyl-8-chloro-4H-s-triazolo 1.5- all 1 .4]benzodiazepine-2-methanol melts at 186.

g. An amount of 16.25 g (0.05 mole) of the alcohol obtained according tof) and 7.6 g (0.075 mole) of triethylamine is dissolved in 200 ml ofabs. methylene chloride. An addition is then made dropwise at 310, withice cooling and stirring. of 8.6 g (0.075 mole) ofmetlianesulphochloride dissolved in 50 ml of abs. methylene chloride.After completion of the dropwise addition. the reaction mixture isheated to 20. and stirred for a further 30 minutes. It is then cooled to5, and 100 m1 of ice-water added. The methylene chloride phase isseparated. and washed three times with 100 m1 of ice-water each time; itis then dried with sodium sulphate and concentrated at 30 in vacuo.

The methanesulphonic acid ester of 6-phenyl-8- chloro-4H-s-triazo1o[1.5-a][ 1 .4lbenzodiazepine-2- methanol is obtained as a dark-yellow.non-crystallising oil. and is further reacted without purification.

EXAMPLE 2 The methanesulphonic acid ester prepared according to Example1 g) from 4.9 g (0.015 mole) of 6-phenyl-8- ch1oro-4H-s-triazo1ol 1.5-a1l 1.4 lbenzodiazepine-Z- methanol and 2.58 g (0.023 mole) ofmethanesulphonic acid chloride is dissolved in 50 m1 of methanol: thesolution is then added dropwise to 100 ml of boiling methanol. which iscontinuously saturated by the introduction of ammonia gas. Refluxing iscarried out for 4 hours with the further introduction of ammonia gas.and the reaction mixture then concentrated in vacuo to dryness. Sodiumhydroxide solution (0.1N) is added to the residue and extractionperformed with benzene. The benzene extract is washed once with water.and at terwards repeatedly extracted with 0.1N acetic acid. The acidextracts are combined. rendered alkaline with conc. ammonia. andextracted with benzene. The combined benzene extracts are washed withwater and with saturated sodium chloride solution. dried over sodiumsulphate. and concentrated to dryness.

The residue of 1.7 g is dissolved in ether/ethanol/triethylamine(3:5:2). and the solution chromatographed on a column of 170 g of silicagel. The employed eluting agent is ether/ethanol/triethylamine (315:2The fractions containing the desired reaction product are combined. andconcentrated in vacuo to dryness. Amorphous2-(aminomethyl)-6-pheny1-8-ch1oro-4H-striazolo[ 1.5-a][1.4]benzodiazepine is obtained. which liquifies at 6975.

EXAMPLE 3 A solution of 6.05 g (0.015 mole) of crude methanesulphonicacid ester of 6-phenyl-8-ch1oro-4H-s-triazolo 1.5-a][ 1.4]benzodiazepine-Z-methanol [produced according to Example 1 g)] in 50ml of dimethylsulphoxide is slowly added dropwise at -1 7 to a solutionof 2.55 g (0.03 mole) ofpiperidine in ml of dimethylsulphoxide: stirringis then carried out for a further 3 hours at room temperature. Thereaction mixture is poured on ice-water. and extracted three times withether. The organic phase is washed twice with water. and once withsaturated sodium chloride solution: it is then dried over sodiumsulphate and concentrated in vacuo to dryness. The residue is dissolvedin benzene/- methylene chloride (1:1). and the solution chromatographedon a column containing 100 g of basic aluminium oxide. elution beingperformed with the same solvent mixture. The fractions containing thedesired reaction product are combined. and concentrated in vacuo.Amorphous Z-(piperidinomethyl)-6-phenyl-8- ch1oro-4H-s-triazolol 1.5-a]1.4]benzodiazepine is obtained. which liquifies at 5564.

The following are obtained analogously from 6.05 g (0.015 mole) of thesame methanesulphonic acid ester:

with 5.4 g (0.077 mole) of pyrrolidinezamorphous 2-[( l-pyrrolidinyll-methyl ]-6-pheny1-8-ch1oro-4H-striazolo 1.5-al[ 1.4]benzodiazepine.which liquifies at 5363;

with 2.61 g (0.030 mole) of morpholinez- 2- (morpholinomethyl)-6-phenyl-8-ch1oro-4H-striazolo[1.5-a][1.4]benzodiazepine. M.P. 11l-113after crystallisation from ether:

with 3.05 g (0.030 mole) of 1-methy1piperazine:- 2-[(4-methy1-l-piperaziny1)-methy1]-6-phenyl-8-ch1oro- 4H-s-triazolo[1.5-a]l 1.4]benzodiazcpine. M.P. 162163 after crystallisation fromether:

with 2.4 g (0.080 mole) of methylaminezamorphous 2-[ methylamino)-methyl ]-6-pheny1-8-chloro-4H-s- 14 triazolo 1.5-a][1.4]benzodiazepine. which liquifies at 56-67.

EXAMPLE 4 Starting with 2.4 g (0.080 mole) of methylamine and 6.32 g(0.015 mole) of crude methanesulphonic acid ester of6-(o-f1uoropheny1)-8-chloro-4H-s-triazolo[ 1.5-a][1.4]benzodiazepine-2-methano1 there is obtained. analogously to theprocedure described in Example 3. 2-[ methylamino )-methyl ]-6-(o-fluorophenyl )-8-. chloro-4H-s-triazo1o[ 1.5-a][ 1.4]benzodiazepine.An addition is made to this compound in 330 ml of ethyl acetate ofethereal hydrogen chloride solution until a sample. to which water hasbeen added. shows a pH- value of ca. 2. After prolonged cooling. theprecipitated crystals are filtered off. and recrystallised twicefromethanol. The hydrochloride obtained after drying contains thedouble-molar amount of crystal water. and melts at 247249.

There is obtained in an analogous manner. starting with 2.4 g (0.08mole) of methylamine and 6.57 g (0.015 mole) of crude methanesulphonicacid ester of 6-(o-ch1orophenyl )-8-ch1oro-4H-s-triazolo[ 1.5-

a][ 1.4]benzodiazepine -2-methanol. 2- [(methy1amino)-methy1]-6-(ch1orophenyl )-8-ch1oro-4H-s-triazolol1.5-a]l1.4]benzodiazepine. This is dissolved in ml ofethanol. and a saturated ethanolic fumaric acid solution added until thepH-value of a sample to which water has been added is ca. 6. Aftercooling. the precipitated crystals are filtered off and recrystallisedonce from methanol. After drying. the obtained2-I(methylamino)-methy1l-6-(o-chloropheny1)- 8-ch1oro-4H-s-triazolo[1.5-a 1.4 lbenzodiazepinefumarate-(2z1 melts at 199201.

The following 2-[(methylamino)-methy1]- compounds are obtained likewiseanalogously to Example 3. by the reaction in each case of 2.4 g (0.080mole) of methylamine with the given amounts (corresponding always to0.015 mole) of the methanesulphonic acid esters (called in short esters)of the stated alcohols:

from 6.05 g of the ester of 6-(o-ch1oropheny1)-4H-striazolo[ 1.5-a][1.4]benzodiazepine-2-methanol:- 2- methylamino )-methyl]-6-(o-ch1orophenyl )-4H-striazolo[ 1.5-a][ 1.4 lbenzodiazepine;

from 7.07 g of the ester of 6-(01.01.a-trifluoro-o-to1yl)-8ch1oro-4H-s-triazolo[ l.5-all 1.4]benzodiazepine-2- methanol:- 2-[methylamino )-methy1]-6-( 01.01.11- trifluoro-o-tolyl)-8-chloro-4H-s-triazolol 1.5- a][ 1.4]benzodiazepine;

from 5.80 g of the ester of 6-phenyl-8-fluoro-4H-striazolo[ 1.5-a][1.4]benzodiazepine-2-methano1:- 2- [(methy1amino )-methyl]-6-pheny1-8-f1uoro-4H-striazolo[ 1.5-a][ 1.4]benzodiazepine'.

from 6.71 g of the ester of 6-phenyl-8-bromo-4H-striazolo[ 1.5-a][1.4lbenzodiazepine-Z-methanolz- 2- [(methylaminol-methyl]-6-phenyl-8-bromo-4H-striazolo[ l.5-a][ 1 .4lbenzodiazepine;

from 6.55 g of the ester of 6pheny1-8- (trifluoromethyl )-4H-s-triazolo[1 .5- a][ 1.4]benzodiazepine-2-methanol:- 2-

[(methylamino )-methy1]-6-pheny1-8- (trifluoromethyl )-4H-s-triazo1o[ 1.5- a][ 1.4 ]benzodiazepine:

from 6.20 g of the ester of 6-pheny1-8-nitro-4H-striazolo[ 1.5-a][1.4]benzodiazepine-2-methano1:- 2-[(methy1amino)-methyl1-6-phenyl-8-nitr0-4H-striazolo[ 1.5-a][ l.41benzodiazepine.

The methanesulphonic acid esters required as starting materials areproduced as follows:

b. The following are obtained analogously to Example l b) with the useof 62.5 g (0.25 mole) of 2-amino-5- chloro-2 '-fluorobenzophenone:- [2-(o-fluorobenzoyl 4-chlorophenylazo 2 chloroacetamido )-malonic aciddiethyl ester;

with the use of 66.5 g (0.25 mole) of 2-amino-2'.5-dichlorobenzophenonez- [2-( o-chlorobenzoyl )-4- chlorophenylazo2-chloroacetamido l-malonic acid diethyl ester;

with the use of 58.0 g (0.25 mole) of 2-amino-2'- chlorobenzophenonez-[o-( o-chlorobenzoyl phenylazo]-(2-chloroacetamidol-malonic acid diethylester;

with the use of 75.0 g (0.25 mole) of 2-amino-5- chloro-2'-(trit'luoromethyl )-benzophenone:- [2-( 01.04.01- trifluoro-o-toluoyl)-4-chlorophenylazo H 2 chloroacetamido)-malonic acid diethyl ester:

with the use of 53.8 g (0.25 mole) of 2-amino-5- fluorobenzophenone:-(2-benzoyl-4-fluorophenylazo)- (2-chloroacetamido)-malonic acid diethylester:

with the use of 69.9 g (0.25 mole) of 2-amino-5- bromobenzophenone:-(2-benzoyl-4- bromophenylazo 2-chloroacetamido )-malonic acid diethylester;

with the use of 66.2 g (0.25 mole) of 2-amino-5-(trifluoromethyl)-benzophenone:- (2-benzoyl-a.a.atrifluoro-p-toylazo2-chloroacetamido l-malonic acid diethyl ester:

with the use of 60.8 g (0.25 mole) of 2-amino-5- nitrobenzophenonez-(2-benzoyl-4-nitrophenylazo 2- chloroacetamido)-malonic acid diethylester.

c. A solution of 8.0 g (0.20 mole) of sodium hydroxide in 400 ml ofwater is added dropwise. in the course of 2 hours. to a solution of 51.2g (0. 10 mole) of [2-(ofluorobenzoyl )-4-chlorophenylazo l-( 2-chloroacetamido)-malonic acid diethyl ester in 600 ml of diosane. Thetemperature of the reaction mixture rises during this time frominitially to a maximum of and the pH-value is finally 8.5 to 9.0. Themixture is stirred at room temperature for a further minutes: it isthereupon neutralised by the addition of glacial acetic acid. andconcentrated in vacuo. Ice and 5 percent sodium bicarbonate solution areadded to the residue: and the mixture then extracted twice with ether.The aqueous phase is retained for further processing. The organic phasesare combined. washed with ice-cold 5 percent sodium bicarbonate solutionand water. dried over sodium sulphate. and concentrated in vacuo. Theresidue is recrystallised from isopropanol. After drying. thel-[2-(o-fluorobenzoyl)-4- chlorophenyl ]-5-( chloromethyl l H- l.2.4-triazole-3- carboxylic acid ethyl ester. obtained as the mainproduct. melts at 97-98.

The above aqueous sodium bicarbonate solutions (the original ones andthe washing-solutions) are combined; 10 percent hydrochloric acid isadded until an acid reaction to a Congo-red indicator is obtained. andthe solution extracted three times with methylene chloride. The combinedorganic extracts are washed with water and with saturated sodiumchloride solution. dried over sodium sulphate. and concentrated invacuo. Crude amorphous 1-[2-(o-fluorobenzoyl)-4-chlorophenyll-5-(chloromethyl)-1H-l.2.4-triazole-3- carboxylic acid isthus obtained as secondary product.

This crude acid can be used direct for cyclisation analogously toExample 1 c) or 1 d).

The following are obtained analogously:

with the use of 52.9 g (0.10 mole) of [2-(0- chlorobenzoyll-4-chlorophenylazo]-( 2- chloroacetamido)-malonic acid diethyl ester:l-[2-(ochlorobenzoyl )-4-chlorophenyl ]-5-( chloromethyl lH-l.2.4-triazole-3-carboxylic acid ethyl ester and the corresponding acid.M.P. l75;

with the use of 49.4 g (0.10 mole) of {o-(ochlorobenzoyl )-phenylazo]-(2-chloroacetamido malonic acid diethyl ester:- 1-lo-(o-chlorobenzoyl)-phenyl l-5-(chloromethyl l H- l .2.4-triazole-3- carboxylic acid ethylester and the corresponding acid:

with the use of 56.2 g (0.10 mole) of l2-(a.a.atrifluoro-o-toluoyl)-4-chlorophenylazo 2- chl'oroacetamido)-malonic acid diethyl ester:-1-l2- 01.0:.a-trifluoro-o-toluoyl )-4-chlorophenyl 1-5 (chloromethyl 1H-] .2.4-triazole-3-carboxylic ethyl ester and the corresponding acid;

with the use of 47.8 g (0.10 mole) of (2-benzoyl-4- fluorophenylazo2-chloroacetamid0 l-malonic acid diethyl ester:- 1-(2-benzoy1-4-fluorophenyl )-5- (chloromethy1)-1 H- 1.2.4-triazole-3-carboxylic acid ethyl ester and the corresponding acid;

with the use of 53.8 g (0.10 mole) of (2-benzoyl-4- bromophenylazo2-chloroacetamido )-malonic acid diethyl ester:-1-(2-benzoyl-4-bromophenyl)-5-(chloromethyll-1H-l.2.4-triazole-3-carboxylic acid ethyl ester and thecorresponding acid:

with the use of 52.8 g (0.10 mole) of(2-benzoyla.a.a-trifluoro-p-tolylazo 2-ch1oroacetamido malonic aciddiethyl ester:-l-(2-benzoyl-a.a.atrifluoro-p-tolyl)-5-(chloromethyl)-lH-1.2.4-triazole-3-carboxylic acid ethyl ester 'and the corresponding acid:

with the use of 50.4 g (0.10 mole) of (2-benzoyl-4-nitrophenylazo)-(2-chloroacetamido)-malonic acid diethyl ester:-1-(2-benzoy1-4-nitrophenyl)-5-(chloromethyl)-1H-1.2.4-triazole-3-carboxylic acid ethyl ester and thecorresponding acid;

d. A solution of 16.88 g (0.04 mole) of 1-[2-(0-fluorobenzoyl)-4-chlorophenyll-5-(chloromethyl)-1H-1.2.4-triazole-3-carboxylic acid ethyl ester and 1 1.2 g (0.08 mole) ofhexamethylentetramine in 250 ml of abs. ethanol is refluxed for 6 hours.The solution is then concentrated at 40 in vacuo; an amount of 800 ml ofice-water is then added to the residue. and extraction performed twicewith methylene chloride. The organic acid phase is washed twice withice-cold 1N hydrochloricacid and three times with water: it is thendried over sodium sulphate and concentrated in vacuo. The residue isrecrystallised from isopropanol. After drying. the obtained6-(o-fluorophenyl )-8-chloro-4H-s-triazolo[ 1.5- a][1.41benzodiazepine-Z-carboxylic acid ethyl ester melts at 177l79.

The following are obtained analogously:

from 17.54 g (0.04 mole) of l-[2-(o-chlorobenzoyl)-4-chlorophenyl1-5-(chloromethyU-l H-l .2.4-triazole- 3-carboxylic acidethyl ester:- 6-(o-chlorophenyl)-8- ch1oro-4H-s-triazolo[ 1.5-a][1.4]benzodiazepine-2- carboxylic acid ethyl ester:

from 16.16 g (0.04 mole) ofl-[o-(o-chlorobenzoyhphenylI-S-(chloromethyU-1H-1.2.4-triazole-3-carboxylic acid ethyl ester:- 6-(o-chlorophenyl)-4H-striazolol l.5-a][1.4]benzodiazepine-2-carboxy1ic acid ethyl ester;

from 18.88 g (0.04 mole) of l-l2-(a.a.a-trifluoro-otoluoyl)-4-chlorophenyll-5-(chloromethyl )-1 H-1 .14- triazole-3-carboxy1icacid ethyl ester:- (w-(cmuxtrifluoro-o-tolyl )-8-chloro-4H-s-triazolol1.5- all 1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:

from 15.50 g (0.04 mole) of 1-(2-benZoyl-4-fluorophenylt-5-(chloromethyl )-1H-1 .2.4triazole-3- carboxylic acidethyl ester:- o-phenyl-8-t1uoro-4H-striazolol 1.5-all1.4]benzodiazepine-Z-carlmxylic acid ethyl ester;

from 17.94 g (0.04 mole) of 1(Z-benzo \'l-4-bromophenyl)-5-(chloromethyl)-1H-1.Z.4-triaZole-3- carboxylic acid ethylester:- (1-pheny1-8-bromo-4H'striazolol 1 .5-all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester.

from 17.50 g (0.04 mole) of l-(l-benzoy'l-mautrifluoro-p-tolyl)-5-(chloromethy1)- 1 H-l .Z.4-triazole- 3-carboxylic acid ethyl ester:-6-phenyl-8- (trifluoromethyl )-4H-s-triazolo[ 1.5- all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester;

from 16.58 g (0.04 mole) of 1-( Z-benzoyl-4nitrophenyl)-5-(chloromethyl)-lH-1.2.4-triazo1e-3- carboxylic acidethyl ester:- h-phenyl-8-nitro-4H-striazolol1.5all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester.

e. and f. The following are obtained analogously' to Examples 1 f) andg):

from 11.54 g (0.03 mole) of fi-(o-lluorophenylH4- ch1oro-4H-s-triazolol1.5-a ll 1.4 lbenzodiazepine-L carboxylic acid ethyl ester:-b-lo-fluorophenyl)-8- chloro-4H-s-triazolol 1.5-a ll 1.4lbenzodiazepine-Z- methanol. M.P. 138145 (from isopropanol) and itsmethanesulphonic acid ester (crude product);

from 12.04 g (0.03 mole) of b-(o-chlorophenyl)-8- chloro-4H-s-triazolol1.5-all 1.4 lbenzodiazepine-Z- carboxylic acid ethyl ester:-6-(o-chlorophenyl)-8- chloro-4H-s-triazolol 1.5-a ll 1.4lbenzodiazepine-Z- methanol and its methanesulphonic acid ester:

from 1 1.0 g (0.03 mole) of b-(o-chlorophenyl )-4H-striazolol 1.5-all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:-o-(o-chlorophenyl)-4H-s-triazo1ol 1.5- all l.4lbenzodiazepine-Z-methanoland its methanesulphonic acid ester:

from 13.04 g (0.03 mole) of 6-(a.a.a-trifluoro-otolyl)-8-chloro-4H-s-triazolol 1.5- all 1.4lbenzodiazepine-Z-carboxylic acidethyl ester:- 6-( a.a.a-trifluoro-o-tolyl )-8-chloro-4H-s-triazolol 1.5-ll1.4]benzodiazepine-Z-methanol and its methanesulphonic acid ester;

from 10.50 g (0.03 mole) of 6-phenyl-8-fluoro-4H-striazolol 1.5-all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:-6-phenyl-8-fluoro-4H-s-triazolol 1.5- all 1.4]benzodiazepine-Z-methanoland its methanesulphonic acid ester:

from 12.33 g (0.03 mole) of 6-pheny1-8-bromo-4H-striazolol 1.5-all1.4lbenzodiazepine-2-carboxylic acid ethyl ester:-o-phenyl-8-bromo-4H-s-triazo1ol1.5- ll 1.4]benzodiazepine-Z-methano1 andits methanesulphonic acid ester:

from 12.0 g (0.03 mole) (trifluoromethyl)-4H-s-triazolo[ 1.5-all1.4lbenzodiazepine-Z-carboxylic acid ethyl ester:- 6-phenyl-8-(tritluoromethyl )-4H-s-triazolo[ 1.5- all l.4lbenzodiazepine- -methanoland its methanesulphonic acid ester:

from 1 1.31 g (0.03 mole) of 6-phenyl-8-nitro-4H-striazolol 1.5-all1.4lbenzodiazepine-Z-carboxylic acid of 6-phenyl-8- ethyl ester:-o-phenyl-8-nitro-4H-s-triazolol 1.5 all 1.4 lbenzodiazepine-Z-methanoland its methanesulphonic acid ester.

EXAMPLE 5 The following are obtained analogously to Example 1:

with the use of 8.41 g of methanesulphonic acid ester of 6-(o-fluorophenyl )-8-ch1oro-4H-s-triazolo| 1.5- all 1.4lbenzodiazepine-Z-methanol:- Z-l(dimethylamino)-methyll-6(o-fluorophenyl1-8- ch1oro-4H-s-triazo1ol1.5-a ll 1.4 lbenzodiazepine. which. after recrystallisation fromether/petroleum ether. melts at 1 141 16; and

with the use of 8.74 g of methanesulphonic acid ester of 6-(o-chlorophenyl )-8-chloro-4H-s-triazolol 1.5- all1.4lbenzodiazepine-Z-methanolz- 2- [(dimethylamino )-methyl l-6-(o-chlorophenyl )-8- chloro-4H-s-triazolol 1.5-all 1.4lbenzodiazepine.

EXAMPLE 6 The following are obtained. analogously to Example 3. by thereaction of 2.55 g (0.03 mole) of piperidine:

with 6.32 g (0.015 mole) of crude methanesulphonic acid ester of6-(o-fluoropheny1)-8-chloro-4H-striazolol 1.5-all 1.4lbenzodiazepine-2-methano1:- 2(piperidinomethyll-o-to-t'luorophenyl)-8-chloro-4H-striazolol 1.5-all1.4lbenzodiazepine; and

with 6.57 g (0.015 mole) ofcrude methanesulphonic acid ester offa-(o-chlorophenyl)-8-chloro-4H-striazolol 1.5-all 1.4lbenzodiazepine-Z-methanol: 2- (piperidinomethyl )-6-( o-chlorophenyl)-8-chloro-4H-striazolol 1.5-all 1.4 lbenzodiazepine.

EXAMPLE 7 a. A solution of 1.69 g (0.0075 mole) of tin(ll)-chloridedihydrate in 24 m1 of 2N sodium hydroxide solution is slowlyadded dropwise at 05 to a solution of 1.75 g (0.005 mole) ofZ-(azidomethyl)6phenyl-8- chloro-4H s-triazolol 1.5-all1.4lbenzodiazepine in 175 ml of percent aqueous ethanol. The reactionmixture immediately becomes cloudy. After completion of the dropwiseaddition. the reaction mixture is stirred fora further 30 minutes at5-1(); it is then neutralised with 2N hydrochloric acid. andconcentrated in vacuo to dryness. Ice and 2N sodium hydroxide solutionare added to the residue. and extraction performed with a mixture ofether/methylene chloride (5:1 The organic phases are extracted with cold1N hydrochloric acid. The acid extracts are combined and 5N sodiumhydroxide solution added until a pH-value of 10 is obtained: extractionis then carried out with ether. The combined ether extracts are washedwith water and with saturated sodium chloride solution. dried oversodium sulphate. and concentrated by evaporation to dryness. AmorphousZ-(aminomethyl)-6-phenyl-8-chloro-4H-striazolol1.5-al[1.4lbenzodiazepine is obtained. which liquifies at 6975.

a. The following are obtained in an analogous manner:

starting with 1.84 g (0.005 mole) of Z-(azidomethyl 6-(o-fluorophenyl)-8-ch1oro-4H-s-triazo1ol 1 .5-

a] [l ,4lbenzodiazepine 2-(aminornethyl)-6 -(ofluorophenyl)-8-chl0ro-4H-s-triazolol 15 all 1 .4lbenzodiazepine: and

starting with 1.92 g (0.005 mole) of Z-(azidomethyl 6-( o-chlorophenyl)-8-chloro-4H-s-triazolol 1.5-

a l .4]benzodiazepine:- Z-aminomethyl )-o-(ochlorophenyl)-8-chloro-4H's-triazolo[ 1.5- a][ l.4]benzodiazepine.

b. The (azidomethyl)-compounds required as starting materials areproduced as follows:

The crude methanesulphonic acid ester produced. according to Example 1g). from 315g (().(ll mole) of 6-phenyl-S-chloro-4H-s-triazolol l.5-a][1.4 lbenzodiazepine-Z-methanol and l.7l g (0.015 mole) ofmethanesulphonic acid chloride is dissolved in 50 ml of acetone. and asolution of3.25 g (0. l 5 mole) of sodium azide in 25 ml of water added.The reaction mixture is stirred for 1 hour at 30. and thereuponconcentrated in vacuo. The obtained crude azidomethyl-compound isdissolved in benzene. and washed once with cold 5 percent sodiumbicarbonate solution and twice with water. The organic solution is driedover sodium sulphate. and concentrated in vacuo. The residue isdissolved in benzene. and the solution chromatographed on a column of 30g of silica gel. elution being performed with benzene. The fractions iswhich the desired reaction product is dissolved are combined. andconcentrated in vacuo. 2-(Azidomethyl)-6-phenyl-8- chloro-4H-s-triazolo[l.5-a][ 1.4] henzodiazepine is obtained as yellow oil. which can befurther reacted direct.

b. 2-(Azidomethyl)-6-(o-fluoro)-8-chloro-4H-striaZoloI l.5-a]ll.4]henzodiazepine and 2-(azidomethyll-o-(o-chlorophenyll-8-chloro-4H-striazololl.5'a][1.4lbenzodiazepine are obtained analogously with the use of thecorresponding crude methanesulphonic acid esters prepared. analogouslyto Example 1 g). with l.7l of g (0.015 mole) of methanesulphochloridefront 3.43 g (().()l mole) of o-(o-fluorophenyl)-8-chloro-4H-s-triazolo[ l .5-a l.4 lbenzodiazepine-Z-methanol. and

3.59 g ((l.()l mole) of 6-(o-chlorophenyl)-8-chloro- -lH-s-triazololl.5-a]l 1.4 ]benzodiazepine-2-methanol. respectively.

What we claim is:

l. A diazepine derivative of the formula 1 2. CH2 N when R- and Rsimultaneously represent alkyl groups as aforesaid. these alkyl groupsmay optionally be bound together in the B- or y-position either directlyor via an oxygen atom or imino group. or alkylimino or hydroxyalkyliminogroup having at most 4 carbon atoms. and wherein each ofthe rings A andB. independently ofthe other; is unsubstituted or substituted by onechlorine atom. fluorine atom. bromine atom. trifluoromethyl group. nitrogroup. alkyl group. or alkoxy group having from 1 to 6 carbon atoms. itsS-oxide and the pharmaceutically acceptable acid addition salts of saiddiazepine derivative or of its S-oxide.

2. A compound according to claim 1 having the formula I. wherein R R-and R have the meanings given in claim 1. and wherein each of the ringsA and B. independently of the other. is unsubstituted or substituted asindicated in claim 1. and the pharmaceutically acceptable acid additionsalts thereof.

3. A compound according to claim 1 having the formula I. wherein R ishydrogen. R and R have the meanings given in claim 1. and wherein eachof the rings A and B. independently of the other. is unsubstituted orsubstituted by one fluorine atom. chlorine atom. bromine atom.trifluoromethyl group or nitro group. and the pharmaceuticallyacceptable acid addition salts thereof.

4. A compound according to claim 1 having the for- R and R have themeanings given in claim 1 and R and R,-.. independently of each other.represent a hydrogen. fluorine. chlorine or bromine atom. atrifluoromethyl or nitro group or an alkyl or alkoxy group having from Ito 6 carbon atoms. its S-oxide and the pharmaceutically acceptable acidaddition salts of said compound of the formula la or of its 5-oxide 5. Acompound having the formula lu given in claim 4. wherein R and R havethe meanings given in claim R. represents a fluorine. chlorine orbromine atom or a nitro or trifluoromethyl group. and

R represents a hydrogen. fluorine. chlorine or bromine atom or atrifluoromethyl group.

6. A compound having the formula la given in claim 4, wherein R and Rindependently of each other. represent a hydrogen atom or an alkyl grouphaving from 1 to 6 carbon atoms. R represents a fluorine. chlorine. orbromine atom or a nitro or trifluoromethyl group. and 5 R represents ahydrogen. fluorine. chlorine or bromine atom or a trifluoromethyl group.and the pharmaceutically acceptable acid addition salts thereof.

7. A compound having the formula lu given in claim 4. wherein R and Rindependently of each other. represent a hydrogen atom or an alkyl grouphaving from 1 to 6 carbon atoms. R represents a chlorine atom in the8-position and R represents hydrogen or a fluorine or chlorine atom inthe ortho-position. and the pharmaceutically acceptable acid additionsalts thereof.

8. A compound having the formula lu given in claim 4. wherein R and Rindependently of each other. represent a hydrogen atom or the methylgroup.

R; represents a chlorine atom in the 8-position and R representshydrogen or a fluorine or chlorine atom in the ortho-position. and thepharmaceutically acceptable acid addition salts thereof.

9. A compound according to claim 1 which is 2- l(dimethylamino )-methyl]-6-phenyl-8-chloro-4H-s- 3o triazolol l.5-a][ l .4 lbenzodiazepine.

10. A compound according to claim 1 which is l- (aminomethyll-(i-phenyl-8-chloro-4H-s-triazolo[ 1.5- all 1.4 lbenzodiazepine.

ll. A compound according to claim 1 which is 2- 35l(methylamino)-methyl]-6-phenyl-8-chloro-4H-striazolol 1.5-aH L4lbenzodiazepine.

12. A compound according to claim 1 which is Z-(piperidinomethyl)-6-phenyl-8-chloro-4H-striazolol 1.5-a H [.4lbenzodiazepine. 4o

13. A compound according to claim 1 which is 2-[( lpyrrolidinyl )-methyll-6-phenyl-8-chloro-4H-striazolol l.5-al[ l .4 lbenzodiazepine.

14. A compound according to claim I which is 2- (morpholinomethyl)-6-phenyl-8-chloro-4H-striazolol l 5-a][ 1.4 Ibenzodiazepine.

15. A compound according to claim 1 which is 2-[ (4- methyl 1-piperazinyl )-methyl ]-6-phenyl-8-chloro-4H- s-triazolol l.5-a][1.4]benzodiazepine.

16. A compound according to claim 1 which is 2- 1(methylamino )-methyl]-6-( o-fluorophenyl )-8-chloro-4H-s-tria7.olo[l.5-a][1.4]benzodiazepine and its hy drochloride. I

17. A compound according to claim 1 which is 2- ltdimethylamino )-methvl ]-6-( o-fluorophenyl )-8- chloro-4H-s-triazolo[ l .5a][ l.4lbenzodiazepine.

18. A compound according to claim 1 which is 2-(aminomethyl)-6-(o-fluorophenyl)-8-chloro--lH-striazolo[ l.5-a][ L4lbenzodiazepine.

19. A compound according to claim 1 which is 2- {(rneth vlamino)-methyll-o-(o-chlorophenyl )-8-chloro- 4H-s-triazolo[ l.5-a][1.4]benzodiazepine and its (2:1

funiarate 20. A compound of the formula IV wherein R represents a loweralkanoyl group. the cyano group. a lower alkoxycarbonyl group. thephenoxycarbonyl. benzyloxycarbonyl. chlorocarbonyl or benzoyl group.

R and R have the meanings given in claim 1 and wherein each of the ringsA and B. independently of the other. is unsubstituted or substituted asindicated in claim 1, and its S-oxide.

1. A DIAZEPINE DERIVATIVE OF THE FORMULA I
 2. A compound according toclaim 1 having the formula I, wherein R1, R2 and R3 have the meaningsgiven in claim 1, and wherein each of the rings A and B, independentlyof the other, is unsubstituted or substituted as indicated in claim 1,and the pharmaceutically acceptable acid addition salts thereof.
 3. Acompound according to claim 1 having the formula I, wherein R1 ishydrogen, R2 and R3 have the meanings given in claim 1, and wherein eachof the rings A and B, independently of the other, is unsubstituted orsubstituted by one fluorine atom, chlorine atom, bromine atom,trifluoromethyl group or nitro group, and the pharmaceuticallyacceptable acid addition salts thereof.
 4. A compound according to claim1 having the formula Ia
 5. A compound having the formula Ia given inclaim 4, wherein R2 and R3 have the meanings given in claim 1, R4represents a fluorine, chlorine or bromine atom or a nitro ortrifluoromethyl group, and R5 represents a hydrogen, fluorine, chlorineor bromine atom or a trifluoromethyl group.
 6. A compound having theformula Ia given in claim 4, wherein R2 and R3, independently of eachother, represent a hydrogen atom or an alkyl group having from 1 to 6carbon atoms, R4 represents a fluorine, chlorine, or bromine atom or anitro or trifluoromethyl group, and R5 represents a hydrogen, fluorine,chlorine or bromine atom or a trifluoromethyl group, and thepharmaceutically acceptable acid addition salts thereof.
 7. A compoundhaving the formula Ia given in claim 4, wherein R2 and R3, independentlyof each other, represent a hydrogen atom or an alkyl group having from 1to 6 carbon atoms, R4 represents a chlorine atom in the 8-position andR5 represents hydrogen or a fluorine or chlorine atom in theortho-position, and the pharmaceutically acceptable acid addition saltsthereof.
 8. A compound having the formula Ia given in claim 4, whereinR2 and R3, independently of each other, represent a hydrogen atom or themethyl group, R4 represents a chlorine atom in the 8-position and R5represents hydrogen or a fluorine or chlorine atom in theortho-position, and the pharmaceutically acceptable acid addition saltsthereof.
 9. A compound according to claim 1 which is2-((dimethylamino)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 10. A compound according to claim 1 which is2-(aminomethyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 11. A compound according to claim 1 which is2-((methylamino)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 12. A compound according to claim 1 which is2-(piperidinomethyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 13. A compound according to claim 1 which is2-((1-pyrrolidinyl)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 14. A compound according to claim 1 which is2-(morpholinomethyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 15. A compound according to claim 1 which is2-((4-methyl-1-piperazinyl)-methyl)-6-phenyl-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
 16. A compound according to claim 1 which is2-((methylamino)-methyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine and its hydrochloride.
 17. A compound according toclaim 1 which is2-((dimethylamino)-methyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1, 4)benzodiazepine.
 18. A compound according to claim 1 which is2-(aminomethyl)-6-(o-fluorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine.
 19. A compound according to claim 1 which is2-((methylamino)-methyl)-6-(o-chlorophenyl)-8-chloro-4H-s-triazolo(1,5-a)(1,4)benzodiazepine and its (2:1)-fumarate.
 20. A compound of the formulaIV